Luciana Pinto Valadares1, Alessandra Christine Vieira Pfeilsticker1, Selma Moreira de Brito Sousa2, Sarah Caixeta Cardoso3, Olivia Laquis de Moraes3, Luiz Claudio Gonçalves de Castro2, Renata Santarem de Oliveira1,2, Adriana Lofrano-Porto4,5. 1. Endocrine Unit, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasília, Brasilia, DF, Brazil. 2. Pediatric Endocrinology Unit, Faculty of Medicine, Department of Pediatrics, University Hospital of Brasília, University of Brasília, Brasilia, DF, Brazil. 3. Molecular Pharmacology Laboratory, Faculty of Health Sciences, University of Brasília, Brasilia, DF, Brazil. 4. Endocrine Unit, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasília, Brasilia, DF, Brazil. adlofrano@unb.br. 5. Molecular Pharmacology Laboratory, Faculty of Health Sciences, University of Brasília, Brasilia, DF, Brazil. adlofrano@unb.br.
Abstract
PURPOSE: 11β-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION: CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11β-hydroxylase deficiency.
PURPOSE: 11β-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION:CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11β-hydroxylase deficiency.
Authors: Paul K Whelton; Robert M Carey; Wilbert S Aronow; Donald E Casey; Karen J Collins; Cheryl Dennison Himmelfarb; Sondra M DePalma; Samuel Gidding; Kenneth A Jamerson; Daniel W Jones; Eric J MacLaughlin; Paul Muntner; Bruce Ovbiagele; Sidney C Smith; Crystal C Spencer; Randall S Stafford; Sandra J Taler; Randal J Thomas; Kim A Williams; Jeff D Williamson; Jackson T Wright Journal: Hypertension Date: 2017-11-13 Impact factor: 10.190
Authors: Maricilda Palandi Mello; Junia Yara Penachioni; Fernando C do Amaral; Margaret de Castro Journal: Arq Bras Endocrinol Metabol Date: 2005-03-07
Authors: K Tsukada; T Ishimitsu; M Teranishi; M Saitoh; M Yoshii; H Inada; S Ohta; M Akashi; J Minami; H Ono; M Ohrui; H Matsuoka Journal: J Hum Hypertens Date: 2002-11 Impact factor: 3.012